Volume 20, Issue 4, December 2004

Table of Contents 20-4

Somatostatin: New Effects on the GH-IGF Axis

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Somatostatin (SRIF) exerts multiple, mostly inhibitory, effects on endocrine and exocrine secretions, gastrointestinal function and cell proliferation. SRIF produced by the hypothalamic parvocellular neurons (paraventricular nucleus) inhibits pituitary growth hormone (GH) release and, subsequently, GH-induced insulin-like growth factor (IGF)-I production.¹ Murray and colleagues performed experiments that elegantly demonstrated peripheral inhibition of hepatic IGF-I production by SRIF and its analog, octreotide. RT-PCR of cDNA from isolated rat hepatocytes revealed expression of both somatostatin receptor subtypes (SSTR) 2 and 3. IGF-I mRNA expression and protein secretion by isolated rat hepatocytes increased in a dose-dependent fashion after incubation with GH. This effect was inhibited by pretreatment with SRIF or octreotide, neither of which affected IGF-I levels without GH, nor affected other GH signaling pathways like phosphorylation of extracellular signal-related kinases (ERK) or induction of c-myc. SRIF or octreotide pretreatment decreased binding of radiolabeled GH to hepatocytes, and also decreased phosphorylation and nuclear localization of STAT5b, the main pathway by which GH induces IGF-I. SRIF inhibition of GH-induced IGF-I required inhibitory G proteins (G_i’s; frequently transduce signals from SSTRs) and involved protein tyrosine phosphorylase (PTP) activation but not increased suppressors of cyotokine signaling (SOCS) 2 or 3. Furthermore, inhibition of GH-induced IGF-I production was confirmed in perfused whole rat livers ex vivo. Both models clearly excluded any central actions of SRIF on the GH/IGF axis.

Murray RD, Kim K, Ren S-G, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest. 2004;114:349–356.

Editor’s Comment: This paper described a new mechanism of action of SRIF and its analogs: the peripheral inhibition of GH-induced hepatic IGF-I production (Figure). SRIF analogs are the primary medical treatment for acromegaly, a state of GH excess usually caused by GH over-expression by a benign pituitary adenoma.² IGF-I elevation may become discordant with GH suppression in some treated patients, and biochemical control may not correlate with clinical improvement. These findings oppose the dogma of SRIF analog action at the hypothalamic-pituitary level. The new data support additional, peripheral action of SRIF and its analogs in suppressing GH-induced IGF-I production. This not only has important implications for the treatment of acromegaly, but also for the potential use of SRIF analogs in the treatment of cancer.^3,4

Adda Grimberg, MD

References - (linked to )

1. Grimberg A, Katz JL. Hypothalamus: neuroendometabolic center. In: Polin R, Fox WW, Abman SH, eds. Fetal and Neonatal Physiology. 3rd Edition. Orlando: Elsevier Science; 2003,1871–1880.
2. Heaney AP, Melmed S. Nature Rev Cancer. 2004;4:285–295.
3. Weckbecker G, Lewis I, Albert R, Schmid HA, Hoyer D, Bruns C. Nature Rev Drug Discov. 2003;2:999–1017.
4. Grimberg A. Cancer Biol Ther. 2004;3:731-733.

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